Project Title

Project Title>

Elucidation and rescue of amygdala abnormalities in the Fmr1 mutant mouse model of fragile X syndrome

Principal Investigator

Principal Investigator

Description

Description

Although the underlying causes of autism spectrum disorders (ASD) are complex, two aspects have emerged from studies over the years: 1) there is a large genetic component to ASD, and 2) ASD is a disorder of brain development. Converging lines of evidence support the hypothesis that mutations in genes that regulate synapse formation and function underlie ASD. One of the best current models for understanding the brain abnormalities in ASD is Fragile X Syndrome (FXS). FXS is a single gene neurodevelopmental disorder that results from an absence of expression of the mRNA binding protein-encoding Fmr1 gene. FXS is characterized by cognitive impairment and impaired social interaction. The latter takes the form of social avoidance/anxiety and/or autistic behavior, which leads to an approximately 45% prevalence of DSM-IV diagnosis of ASD in boys with FXS, thus making FXS the leading known genetic cause of autism. Therefore, although most cases of ASD likely involve interactions between multiple genetic pathways, the behavioral similarities and involvement of overlapping brain regions indicates that the study of FXS at the experimental or clinical level will contribute significantly to understanding the developmental alterations that occur in autism. The proposed research is directed toward the study of synaptic alterations in inhibitory transmission in the amygdala in the Fmr1 mutant animal model of FXS with two goals: 1) determination of the mechanism of altered inhibitory neurotransmission and 2) correction of these defects. This will be accomplished by a multidisciplinary approach combining electrophysiology, immunohistochemistry, neuroanatomy, mouse genetics and pharmacology. As approximately 45% in boys with FXS are autistic, the study of FXS and animal models of FXS is one of the best current approaches for understanding the biological underpinnings of autism.